Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US. There is no effective treatment for the most prevalent atrophic (dry) form of AMD. The loss of vision in atrophic AMD is caused by degeneration of photoreceptor cells (rods and cones) in the central part of the retina called macula. Preservation of macular rods and cones is the ultimate goal of AMD treatment. NR2E3 is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the retina where it is involved in photoreceptor maintenance and differentiation. Our overall objective is to identify a small molecule NR2E3 agonist suitable for performing proof-of-concept photoreceptor protection experiments in animal models of retinal degeneration. Identification of NR2E3 agonists will also provide an important pharmacological tool for probing basic biologic mechanisms of photoreceptor development and differentiation. The studies outlined in this proposal seek to develop an HTRF assay for agonist-induced release of corepressor NCOR from the NR2E3-NCOR complex (Specific Aim 1) and to adapt this assay to the HTS format suitable for screening of a compound collection at one of the NIH MLSCN screening centers (Specific Aim 2).